The present invention relates to novel hexanoic acid derivatives, methods of use and pharmaceutical compositions containing them.
The compounds of the invention are potent and selective inhibitors of MIP-1xcex1 binding to its receptor CCR1 found on inflammatory and immunomodulatory cells (preferably leukocytes and lymphocytes). The CCR1 receptor is also sometimes referred to as the CC-CKR1 receptor. These compounds also inhibit MIP-1xcex1 (and the related chemokines shown to interact with CCR1 (e.g., RANTES and MCP-3)) induced chemotaxis of THP-1 cells and human leukocytes and are potentially useful for the treatment or prevention of autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult Respiratory Distress Syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), chronic bronchitis, xeno-transplantation, transplantation tissue rejection (chronic and acute), organ rejection (chronic and acute), atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis).
MIP-1xcex1 and RANTES are soluble chemotactic peptides (chemokines) which are produced by inflammatory cells, in particular CD8+ lymphocytes, polymorphonuclear leukocytes (PMNS) and macrophages, J. Biol. Chem., 270 (30) 29671-29675 (1995). These chemokines act by inducing the migration and activation of key inflammatory and immunomodulatory cells. Elevated levels of chemokines have been found in the synovial fluid of rheumatoid arthritis patients, chronic and rejecting tissue transplant patients and in the nasal secretions of allergic rhinitis patients following allergen exposure (Teran, et al., J. Immunol., 1806-1812 (1996), and Kuna et al., J. Allergy Clin. Immunol. 321 (1994)). Antibodies which interfere with the chemokine/receptor interaction by neutralizing MIP1xcex1 or gene disruption have provided direct evidence for the role of MIP-1xcex1 and RANTES in disease by limiting the recruitment of monocytes and CD8+ lymphocytes (Smith et al., J. Immunol, 153, 4704 (1994) and Cook et al., Science, 269, 1583 (1995)). Together this data demonstrates that CCR1 antagonists would be an effective at treatment of several immune based diseases. The compounds described within are potent and selective antagonists of CCR1.
The present invention relates to compounds of the formula 
or the pharmaceutically acceptable salt thereof; wherein
R1 is (C2-C9)heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, deuterium, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alky]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
R2 is phenyl-(CH2)mxe2x80x94, naphthyl-(CH2)mxe2x80x94, (C3-C10)cycloalkyl-(CH2)mxe2x80x94, (C1-C6)alkyl or (C2-C9)heteroaryl-(CH2)mxe2x80x94, wherein m is an interger from zero to four; wherein each of said phenyl, naphthyl, (C3-C10)cycloalkyl or (C2-C9)heteroaryl moieties of said phenyl-(CH2)mxe2x80x94, naphthyl-(CH2)mxe2x80x94, (C3-C10)cycloalkyl-(CH2)mxe2x80x94 or (C2-C9)heteroaryl-(CH2)mxe2x80x94 groups may optionally be substituted with one or more substituents independently selected from hydrogen, deuterium, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, phenoxy, benzyloxy, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
R3 is hydrogen, deuterium, (C1-C10)alkyl, (C3-C10)cycloalkyl-(CH2)nxe2x80x94, (C2-C9)heterocycloalkyl-(CH2)nxe2x80x94, (C2-C9)heteroaryl-(CH2)nxe2x80x94 or aryl-(CH2)nxe2x80x94; wherein n is an interger from zero to six;
wherein said R3 (C1-C10)alkyl group may optionally be substituted with one or more substituents, independently selected from hydrogen, deuterium, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(C∇O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2-(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl; and wherein any of the carbon-carbon single bonds of said (C1-C10)alkyl may optionally be replaced by a carbon-carbon double bond;
wherein the (C3-C10)cycloalkyl moiety of said R3 (C3-C10)cycloalkyl-(CH2)nxe2x80x94 group may optionally be substituted by one to three substitutents independently selected from the group consisting of hydrogen, deuterium, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkylxe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
wherein the (C2-C9)heterocycloalkyl moiety of said R3 (C2-C9)heterocycloalkyl-(CH2)nxe2x80x94group may contain from one to three heteroatoms independently selected from nitrogen, sulfur, oxygen,  greater than S(xe2x95x90O),  greater than SO2 or  greater than NR6, wherein said (C2-C9)heterocycloalkyl moiety of said (C2-C9)heterocycloalkyl-(CH2)nxe2x80x94 group may optionally be substituted on any of the ring carbon atoms capable of forming an additional bond with a substituent independently selected from the group consisting of hydrogen, deuterium, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
wherein the (C2-C9)heteroaryl moiety of said R3 (C2-C9)heteroaryl-(CH2)nxe2x80x94 group may contain from one to three heteroatoms independently selected from nitrogen, sulfur or oxygen wherein said (C2-C9)heteroaryl moiety of said (C2-C9)heteroaryl-(CH2)nxe2x80x94 group may optionally be substituted on any of the ring carbon atoms capable of forming an additional bond with a substituent selected from the group consisting of hydrogen, deuterium, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl; and
wherein said aryl moiety of said R3 aryl-(CH2)nxe2x80x94 group is optionally substituted phenyl or naphthyl, wherein said phenyl and naphthyl may optionally be substituted with from one to three substituents independently selected from the group consisting of hydrogen, deuterium, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
or R3 and the carbon to which it is attached form a five to seven membered carbocyclic ring, wherein any of the carbon atoms of said five membered carbocyclic ring may optionally be substituted with a substituent selected from the group consisting of hydrogen, deuterium, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl(Oxe2x95x90C)xe2x80x94Oxe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C9)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl; wherein one of the carbon-carbon bonds of said five to seven membered carbocyclic ring may optionally be fused to an optionally substituted phenyl ring, wherein said substitutents may be independently selected from hydrogen, deuterium, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), hydroxy, hydroxy-(C1-C8)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms (preferably one to three fluorine atoms), (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl; and
R4 is (C2-C9)heteroaryl , (C2-C9)heterocycloalkyl, R5R6N-sulfonyl or a group of the formula 
wherein R5 is hydrogen, deuterium, (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(CH2)pxe2x80x94, (C2-C9)heterocycloalkyl-(CH2)pxe2x80x94, (C2-C9)heteroaryl-(CH2)pxe2x80x94, phenyl-(CH2)pxe2x80x94, or naphthyl-(CH2)pxe2x80x94, wherein p is an integer from zero to four; wherein said (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl, phenyl and naphthyl groups of said (C2-C9)heterocycloalkyl-(CH2)pxe2x80x94, (C2-C9)heteroaryl-(CH2)pxe2x80x94, phenyl-(CH2)pxe2x80x94, or naphthyl-(CH2)pxe2x80x94 may be optionally substituted on any of the ring atoms capable of supporting an additional bond with a substituent selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C8)alkyl, (C1-C6) alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2 amino, amino(C1-C6)alkyl, (C1-C6)alkylamino (C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C8)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl (Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C8)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
or R5 and R6 together with the nitrogen atom to which they are attached form a (C2-C9)heterocycloalkyl group wherein any of the ring atoms of said (C2-C9)heterocycloalkyl group may optionally be substituted with a substituent selected from the group consisting of hydrogen, halo, CN, (C1-C6)alkyl optionally substituted with one or more fluorine atoms, hydroxy, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy optionally substituted with one or more fluorine atoms, (C1-C6)alkoxy(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94, H(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, (C1-C6) alkyl(Oxe2x95x90C)xe2x80x94, (C1-C6)alkyl(Oxe2x95x90C)xe2x80x94(C1-C6)alkyl, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2 amino, amino(C1-C6)alkyl, (C1-C6)alkylamino (C1-C6)alkyl, [(C1-C6)alkyl]2amino(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, H2Nxe2x80x94SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, (C1-C6)alkylHNxe2x80x94SO2xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94SO2xe2x80x94(C1-C6)alkyl, CF3SO3xe2x80x94, (C1-C6)alkyl-SO3xe2x80x94, phenyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, and (C2-C9)heteroaryl;
R6 is hydrogen, deuterium, (C1-C6)alkyl or amino;
X is NR7 or S wherein R7 is defined as R4 above; and
with the proviso that when R4 is a five-membered heterocyclic group, either R2 or R3 must be substituted by a functional group other than (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, amino(C1-C6)alkyl, benzofuryl, indolyl, azacycloalkyl, azabicycloalkyl or benzopiperidinyl.
The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3- naphthoate)]salts.
The invention also relates to base addition salts of formula I. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
The compounds of this invention may contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof.
Unless otherwise indicated, the alkyl and alkenyl groups referred to herein, as well as the alkyl moieties of other groups referred to herein (e.g., alkoxy), may be linear or branched, and they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or be linear or branched and contain cyclic moieties. Unless otherwise indicated, halogen includes fluorine, chlorine, bromine, and iodine.
(C3-C10)Cycloalkyl when used herein refers to cycloalkyl groups containing zero to two levels of unsaturation such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1]octane, norbornanyl etc.
(C2-C9)Heterocycloalkyl when used herein refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl, etc. One of ordinary skill in the art will understand that the connection of said (C2-C9)heterocycloalkyl rings is through a carbon or a sp3 hybridized nitrogen heteroatom.
(C2-C9)Heteroaryl when used herein refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7, 8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl; etc. One of ordinary skill in the art will understand that the connection of said (C2-C9)heterocycloalkyl rings is through a carbon atom or a sp3 hybridized nitrogen heteroatom.
Aryl when used herein refers to phenyl or naphthyl.
The compounds of this invention include all conformational isomers (e.g., cis and trans isomers) and all optical isomers of compounds of the formula I (e.g., enantiomers and diastereomers), as well as racemic, diastereomeric and other mixtures of such isomers.
Preferred compounds of the of formula I include those with the stereochemistry depicted in formula 
Preferred compounds of the formula I include those wherein R1 is optionally substituted pyrazolo[3,4-b]pyridinyl, cinnolinyl, pyridinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzothiazolyl, indolyl, pyrazinyl, benzoimidazolyl, benzofuranyl, benzo[b]thiophenyl, naphthalenyl, quinoxalinyl, isoquinolinyl, 5,6,7,8-tetrahydro-quinolin-3-yl or quinolinyl, more preferably pyrazolo[3,4-b]pyridin-5-yl, cinnolin-4-yl, pyridin-2-yl, 6,7-dihydro-5H-[1]pyrindin-3-yl, benzothiazol-2-yl, indol-2-yl, pyrazin-2-yl, benzoimidazol-2-yl, benzofuran-2-yl, benzo[b]thiophen-2-yl, naphthalen-2-yl, quinoxalin-2-yl, quinoxalin-6-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, 5,6,7,8-tetrahydro-quinolin-3-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl or quinolin-6-yl, most preferably quinoxalin-6-yl, quinolin-2-yl, quinolin-3-yl, quinoxalin-2-yl, quinolin-4-yl or quinolin-6-yl.
Other preferred compounds of formula I include those wherein R2 is optionally substituted phenyl, benzyl, naphthyl, cyclohexyl, thienyl, thiazolyl, pyridyl, oxazolyl, furanyl, or thiophenyl; wherein said substituents are independently selected from hydrogen, halo, (C1-C6)alkyl, trifluoromethyl, trifluoromethoxy, hydroxy, xe2x80x94C(xe2x95x90O)xe2x80x94OH, (C1-C6)alkoxy, (C1-C6)alkoxy(Cxe2x95x90O)xe2x80x94, NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94(C1-C6)alkyl, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, (C1-C6)alkyl-HN(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, [(C1-C6)alkyl]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94(C1-C6)alkyl, H(Oxe2x95x90C)xe2x80x94NHxe2x80x94, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94NH, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[NH](C1-C6)alkyl, (C1-C6)alkyl(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl](C1-C6)alkyl, phenoxy, and benzyloxy.
Other preferred compounds of formula I include those wherein R3 is optionally substituted (C1-C10)alkyl, benzyl, pyranyl or (C3-C10)cycloalkyl-(CH2)nxe2x80x94, wherein any of the carbonxe2x80x94carbon single bonds of said (C1-C10)alkyl may be optionally replaced by a carbonxe2x80x94carbon double bond; more preferably optionally substituted n-butyl, isobutyl, n-pentyl, 3-methyl-butyl, 2-methyl-pentyl, allyl, cyclopentyl, cyclohexyl or cycloheptyl, more preferably wherein the substituent is fluoro, (C1-C6)alkyl or hydroxy.
Examples of specific preferred compounds of the formula I are the following:
Quinoxaline-2-carboxylic acid [1(S)-(3-fluoro-benzyl)-2(S),7-dihydroxy-4(R)-(1H-imidazol-2-yl)-7-methyl-octyl]-amide;
Quinoxaline-2-carboxylic acid [1(S)-benzyl-2(S),7-dihydroxy-4(R)-(1H-imidazol-2-yl)-7-methyl-octyl]-amide;
Quinoxaline-2-carboxylic acid [7-fluoro-1(S)-(3-fluoro-benzyl)-2(S)-hydroxy-4(R)-(1H-imidazol-2-yl)-7-methyl-octyl]-amide;
Quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-2(S)-hydroxy-4(R)-(1H-imidazol-2-yl)-7-methyl-octyl]-amide;
Quinoxaline-2-carboxylic acid [1(S)-(3-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-4(R)-sulfamoyl-octyl]-amide;
Quinoxaline-2-carboxylic acid (1(S)-benzyl-2(S),7-dihydroxy-7-methyl-4(R)-sulfamoyl-octyl)-amide;
Quinoxaline-2-carboxylic acid [7-fluoro-1(S)-(3-fluoro-benzyl)-2(S),-hydroxy-7-methyl-4(R)-sulfamoyl-octyl]-amide;
Quinoxaline-2-carboxylic acid (1(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-sulfamoyl-octyl)-amide;
Quinoxaline-2-carboxylic acid [1(S)-(3-fluoro-benzyl)-(2(S),7-dihydroxy-7-methyl-4(R)-methylsulfamoyl-octyl]-amide;
Quinoxaline-2-carboxylic acid (1(S)-benzyl-2(S)-7-dihydroxy-7-methyl-4(R)-methylsulfamoyl-octyl)-amide;
Quinoxaline-2-carboxylic acid [(S)-(3-fluoro-benzyl)-2(S),7-hydroxy-7-methyl-4(R)-methylsulfamoyl-octyl]-amide;
Quinoxaline-2-carboxylic acid [I(S)-benzyl-7-fluoro-2(S)-hydroxy-7-methyl-4(R)-methylsulfamoyl-octyl]-amide;
Quinoxaline-2-carboxylic acid [4(R)-(4-chloro-1 H-imidazol-2-yl )-1 (S)-(3-fluoro-benzyl)-2(S),-7-fluoro-benzyl)-2(S)-hydroxy-dihydroxy-7-methyl-octyl]-amide;
Quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)(4-chloro-1H-imidazol-2-yl)-2(S),-7-hydroxy-7-methyl-octyl]-amide;
Quinoxaline-2-carboxylic acid [4(R)-(4-chloro-1H-imidazol-2-yl)-7-fluoro-1(S)-(3-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;
Quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)(4-chloro-1H-imidazol-2-yl)-7-fluoro-2(S)-hydroxy-7-methyl-octyl]-amide;
Quinoxaline-2-carboxylic acid [1(S)-(3-fluoro-benzyl)-4(R)-(4-fluoro-1H-imidazol-2-yl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;
Quinoxaline-2-carboxylic acid [1(S)-benzyl-4(R)-(4-fluoro-1H-imidazol-2-yl)-2(S)-7-dihydroxy-7-methyl-octyl]amide;
Quinoxaline-2-carboxylic acid [7-fluoro-1(S)-(3-fluoro-benzyl)-4(R)-(4-fluoro-1H-imidazol-2-yl)-2(S)-hydroxy-7-methyl-octyl]-amide; and
Quinoxaline-2-carboxylic acid [1(S)-benzyl-7-fluoro-4(R)-(4-fluoro-1H-imidazol-2-yl)-2(S)-hydroxy-7-methyl-octyl]amide.
The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition selected from autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult respiratory distress syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), chronic bronchitis, xeno-transplantation, transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis). in a mammal, preferably a human, comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating or preventing such disorder or condition and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by inhibiting MIP-1xcex1 binding to the receptor CCR1 in a mammal, preferably a human, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such disorder or condition and a pharmaceutically acceptable carrier. Examples of such disorders and conditions are those enumerated in the preceding paragraph.
The present invention also relates to a method for treating or preventing a disorder or condition selected from autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult respiratory distress syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), chronic bronchitis, xeno-transplantation, transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis) in a mammal, preferably a human, comprising administering to a mammal in need of such treatment or prevention an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder or condition.
The present invention also relates to a method for treating or preventing a disorder or condition that can be treated or prevented by antagonizing the CCR1 receptor in a mammal, preferably a human, comprising administering to a mammal in need of such treatment or prevention an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder or condition.
The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition selected from autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult respiratory distress syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), chronic bronchitis, xeno-transplantation, transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis) in a mammal, preferably a human, comprising a CCR1 receptor antagonizing effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by antagonizing the CCR1 receptor in a mammal, preferably a human, comprising a CCR1 receptor antagonizing effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a method for treating or preventing a disorder or condition selected from autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult respiratory distress syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), chronic bronchitis, xeno-transplantation, transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis) in a mammal, preferably a human, comprising administering to a mammal in need of such treatment or prevention a CCR1 receptor antagonizing effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.